Zofenopril is a non-peptidic orally active sulphydryl ACE inhibitor with long lasting action for the treatment of hypertension. It is currently approved in the form of the calcium salt for the treatment of hypertension.
Prior art forms of zofenopril calcium comprise a monohydrate form designated form C disclosed in international patent application WO 2007/003963 and two anhydrous forms both disclosed in U.S. Pat. Nos. 6,515,012 and 6,521,760 and designated forms A and B.
One requirement of a pharmaceutically acceptable active ingredient is that it should have an advantageous dissolution profile which is an important contributory factor in the bioavailability of a pharmaceutical compound. There are many avenues open to the skilled person in order to enhance the dissolution profile of an active pharmaceutical ingredient (API) and subsequently a pharmaceutical composition containing the API. These include reducing the particle size of the API, adding a surfactant to the composition or utilising different forms of the compound such as salts, solvates or crystalline forms having an advantageous dissolution profile. This latter route forms the basis of the present application. It is generally expected by those skilled in the art that hydrated forms of a chemical compound usually exhibit decreased solubility levels in aqueous media compared to anhydrous forms. Thus, it is advantageous to provide stable anhydrous forms of a pharmaceutical compound.
U.S. Pat. Nos. 6,515,012 and 6,521,760 discuss the prior art disclosed in U.S. Pat. No. 4,316,906 and describe the method for the preparation of zofenopril calcium as disclosed in U.S. Pat. No. 4,316,906 as comprising the following steps:    (a) condensation between cis-4-(phenylthio)-L-proline and D-3-(benzoylthio)-2-methylpropionyl chloride in aqueous solution keeping the pH at values of 8-8.5 by addition of 5N sodium hydroxide, subsequent acidification with HCl, extraction with isobutyl acetate and concentration of the extracts, washing with saline solution, to give (4S)-1-[(2S)-3-(benzoylthio)-2-methylpropinoyl]-4-(phenylthio)-L-proline;    (b) treatment of the resinous material from the previous step in isopropanol solution with potassium 2-ethyl-hexanoate to obtain the corresponding potassium salt;    (c) dissolution of the potassium salt in water to a 5% concentration and very slow addition, with simultaneous seeding, of a slight excess of a 2N calcium chloride aqueous solution to precipitate the desired calcium salt, washing the resulting product thoroughly with water, drying under vacuum at a comparatively high temperature to give the desired calcium salt as dry powder with a melting point of about 250° C.;    (d) alternatively (4S)-1-[(2S)-3-(benzoylthio)-2-methylpropinoyl]-4-(phenylthio)-L-proline is dissolved in ethanol and treated with the same volume of an aqueous suspension containing one equivalent of calcium oxide; after removing ethanol and subsequently washing with ether, the aqueous suspension is freeze-dried to obtain the calcium salt with a melting point of 235-237° C.
According to U.S. Pat. Nos. 6,515,012 and 6,521,760, the synthesis described in U.S. Pat. No. 4,316,906 (cited above at points a, b and c) mainly yields polymorph A, but also polymorph B in very variable percentages and never below 20%. Moreover, the alternative synthesis described (cited at point d) affords a partially amorphous product with very variable characteristics, in which polymorph A, when present, is in concentrations much lower than those obtained in the preceding process.
U.S. Pat. Nos. 6,515,012 and 6,521,760 both disclose a process for the preparation of substantially pure polymorph A of zofenopril calcium comprising the following steps:    (a) reaction of (S)(−)-3-(benzoylthio)-2-methyl-propanoic acid chloride and cis-4-(phenylthio)-L-proline in water at a pH ranging from 9.0-9.5 and recovery of zofenopril in the acidic form,    (b) salification of acid zofenopril with a potassium salt in alcoholic solution and recovery of the resulting potassium salt,    (c) conversion of the potassium salt to calcium by addition of an aqueous solution of zofenopril potassium salt to a calcium chloride aqueous solution at 70-90° C. with simultaneous seeding to promote the precipitation of polymorph A.
The synthesis disclosed in the aforementioned US patents for the preparation of polymorph A has the following drawbacks:                The reaction is carried out at a relatively high temperature (80-85° C.) at which inter-conversion of the polymorphs is possible.        Substantially pure polymorph A can be obtained from the above process, but the possibility of traces of polymorph B cannot be ruled out.        
The aforementioned US patents also disclose a process for the preparation of polymorph B comprising the following steps:    (a) A solution of zofenopril potassium salt (0.27M) is sprayed in lukewarm water (55° C.), while adding a calcium chloride solution, the solution being such that the total amounts of drug and calcium chloride are equimolar.    (b) The resulting suspension containing the slurry product is heated at 85° C. for 12-14 hours to obtain complete conversion to polymorph B.    (c) After cooling at about 25° C., the product is filtered, washed with water until it is substantially free from chloride ions, and then dried under vacuum.
The present inventors have found the following potential and actual disadvantages with the prior art forms A and B:                The absorption of considerable amounts of moisture can lead to the reversion to a hydrated form.        The absorption of moisture can result in ‘sticky’ compounds that are a problem during formulation of the compound into pharmaceutical combinations.        The absorption of considerable amounts of water can have an impact on the dissolution profile and cause an inconsistent dissolution profile.        The absorption of moisture can induce degradation processes not only of the API, but also of potentially susceptible excipients that may be used in the drug product.        
Thus, it would be advantageous to provide novel anhydrous crystalline forms of zofenopril calcium that are essentially non-hygroscopic and can overcome the problems associated with the prior art forms. It would also be advantageous to provide a compound that shows increased dissolution kinetics and is hygroscopically stable.